Responding to BCR-ABL kinase, et al

[Guest guest]

Previous work by senior author J. Donato, PhD, from the University of

Michigan Comprehensive Cancer Center, in Ann Arbor, showed that LYN kinase

regulates the survival and responsiveness of CML cells to the inhibition of

BCR-ABL kinase, and that there are differences in LYN regulation between

imatinib-sensitive and imatinib-resistant CML cell lines. (Blood.

2003;101:690-698). Although LYN overexpression and activation was demonstrated

in cells isolated from CML patients with disease progression and imatinib

resistance, the role and extent of the association between LYN and clinical

responses to imatinib remain unclear. Results from mutational studies of

BCR-ABLassociation and mechanism of imatinib resistance warrants further study

in additional patients.

http://www.medscape.com/viewarticle/576661

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Imatinib Resistance and Second Generation Drugs: Mutations that cause imatinib

resistance are usually those that lead to a BCR-ABL protein with a functional

ABL tyrosine kinase domain, but that totally abrogate or impair drug binding. On

the molecular level, point mutations in BCR-ABL reduce the binding of imatinib

to the protein by either a direct or an indirect mechanism. In the case of

direct mechanisms, mutations are clustered around the imatinib binding site,

which partially overlaps that of ATP, and reduce imatinib binding either as a

result of changes to amino-acid side-chains, which contribute favourable

lipophilic contacts or hydrogen-bond (H-bond) interactions, or as a result of

topographical changes that sterically hinder imatinib binding. Examples of

residues that inhibit imatinib binding when they are mutated are Thr315 and

Phe317 (Ref. 5) ( Table 1 ).

http://www.medscape.com/viewarticle/559294_2________________________________

Overexpression of BCR-ABL mRNA and protein: The expansion of mutant clones in

imatinib-treated patients is often prognostic for relapse and disease

progression.

Based on a crystal structure of an analogue of imatinib bound to the ABL kinase

domain,[12] Druker and co-workers[13] had previously recognized this residue as

being crucial for the interaction of imatinib with ABL, and found that mutation

to valine (T315V) resulted in a catalytically active kinase domain that was

substantially less sensitive to imatinib compared with the wild-type enzyme. The

Thr315 residue is located at the gatekeeper position at the periphery of the

nucleotide-binding site of the protein, and participates, through the

hydroxymethylene side-chain, in a crucial H-bond interaction between imatinib

and ABL,[12] as well as BCR-ABL.[14,15] Mutation to isoleucine abrogates the

possibility of this H-bond interaction, which, combined with the additional bulk

of the isoleucine side-chain, sterically hinders imatinib binding and leads to

imatinib insensitivity and consequently resistance.

http://www.medscape.com/viewarticle/559294_3

Good read,

Lottie